ARTICLES
1H), 2.13 (s, 3H), 1.94 (dd, J ¼ 13.5, 6.0 Hz, 1H), 1.66 (bs, 2H); 1.64 (td, J ¼ 13.5,
6.0 Hz, 1H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR: (125 MHz, CDCl3) d 178.4, 173.5,
170.0, 86.3, 84.1, 79.9, 70.7, 67.4, 55.1, 54.1, 47.9, 37.4, 35.3, 28.5, 20.8, 19.2, 15.9; IR
(film, cm21): 3,464, 2,929, 2,872, 2,854, 1,765, 1,749, 1,462, 1,377, 1,329, 1,284,
1,236, 1,186, 1,115, 1,070, 1,036, 982; HRMS (ESI) m/z calc’d for C17H22O8Na
[M þ Na]þ: 377.1212, found 377.1220; [a]2D5 ¼ þ104.78 (c ¼ 0.47, EtOH).
carbon-centred substrate radicals, had been limited to enzymatic
catalysis. Our results underscore that, due to mechanistic similarities
with oxidation enzymes found in nature, the biomimetic small mol-
ecule Fe(PDP) catalyst has the capacity to interrogate natural
product biosynthesis performed by such enzymes.
We postulate that the intramolecular nature of Fe(PDP) C–H
activation with carboxylic acid substrates alters the orientation of
the substrate radical during the hydroxyl rebound step and diverts
reactivity towards a second hydrogen abstraction to furnish olefin
intermediates. Knowledge of the subtle substrate/catalyst inter-
actions required for promoting desaturation will aid in the develop-
ment of new metal catalysts for aliphatic C–H desaturation.
Received 13 September 2010; accepted 9 December 2010;
published online 23 January 2011
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Methods
C–H oxidation of picrotoxinin derivative 30. Into a 40 ml borosilicate vial was
added acid 30 (71.4 mg, 0.21 mmol, 1.0 equiv.), followed by 5 mol% Fe(S,S-PDP) 1
(10.3 mg, 0.011 mmol, 0.05 equiv.), 0.32 ml CH3CN and a magnetic stir bar. While
the resulting deep-red solution stirred, a solution of H2O2 (50 wt% in H2O, 14.5 ml,
0.25 mmol, 1.2 equiv.) in 1.9 ml CH3CN was added over a period of 1 min (dropwise
addition for 45 s, followed by streamwise addition for 15 s), generating an amber-
brown solution. Stirring followed for 10 min at ambient temperature, then a solution
of 5 mol% 1 (10.3 mg, 0.011 mmol, 0.05 equiv.) in 0.2 ml CH3CN was added in one
burst. A second solution of H2O2 (50 wt% in H2O, 14.5 ml, 0.25 mmol, 1.2 equiv.) in
1.9 ml CH3CN was added as before and stirred for 10 min. Following this stirring
period, a second solution of 5 mol% 1 (10.3 mg, 0.011 mmol, 0.05 equiv.) in 0.2 ml
CH3CN was added in one burst, followed by a third solution of H2O2 (50 wt% in
H2O, 14.5 ml, 0.25 mmol, 1.2 equiv.) in 1.9 ml CH3CN. The reaction was stirred for a
final 10 min and was analysed by thin layer chromatography (TLC). The crude
reaction mixture was filtered through a short silica plug (100% EtOAc) and 1H
nuclear magnetic resonance (NMR) analysis indicated a mixture of hydroxylactone
diastereomers (run 1, 1.6:1 d.r.; run 2, 1.5:1 d.r.; average, 1.6:1 d.r. (32a/32b, 1H
NMR, acetone-d6). Flash chromatography with silica gel (gradient, 20% ꢀ 30% ꢀ
50% acetone/hexanes) was used to isolate the lactone product as white crystals (run
1: 26.1 mg, 0.077 mmol, 37% yield; run 2, 74.2 mg scale: 29.1 mg, 0.086 mmol, 39%
yield; average: 38% yield), together with a mixture of hydroxylactones 32a and 32b
(run 1: 29.6 mg, 0.084 mmol, 40% yield; run 2: 29.7 mg, 0.084 mmol, 38% yield;
average: 39% yield). The hydroxylactone diastereomers could be separated by MPLC
(gradient, 0 ꢀ 50% acetone/hexanes) to obtain pure samples for
spectroscopic analysis.
Lactone [(1)-31]. 1H NMR (500 MHz, CDCl3) d 5.10 (dd, J ¼ 11.8, 3.8 Hz, 1H),
4.62 (d, J ¼ 4.0 Hz, 1H), 2.80 (d, J ¼ 15.0 Hz, 1H), 2.76 (d, J ¼ 7.5 Hz, 1H), 2.68
(bs, 1H), 2.50 (dd, J ¼ 14.5, 6.5 Hz, 1H), 2.30–2.35 (m, 1H), 2.19 (dd, J ¼ 12.3,
5.8 Hz, 1H), 2.13 (s, 3H), 1.95 (dd, J ¼ 13.3, 5.3 Hz, 1H), 1.59 (td, J ¼ 13.5, 5.8 Hz,
1H), 1.53 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H); 13C NMR: (125 MHz, CDCl3) d 178.5,
173.7, 170.0, 84.5, 84.2, 79.8, 70.8, 55.0, 54.1, 48.3, 44.0, 35.3, 28.7, 28.5, 20.7, 20.5,
19.1; IR (film, cm21): 3,489 (broad), 2,954, 2,922, 2,854, 1,780, 1,739 (2 peaks),
1,464, 1,377, 1,263, 1,240, 1,174, 1,120, 1,072, 1,036; HRMS (ESI) m/z calc’d for
C17H23O7 [M þ H]þ: 339.1444, found 339.1448; [a]D25 ¼ þ130.18 (c ¼ 1.22, CHCl3).
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theoretical study identifies the stereoelectronic factor that controls the switch
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Hydroxylactone [(1)-32a]. 1H NMR (500 MHz, CDCl3) d 5.48 (dd, J ¼ 12.0,
3.5 Hz, 1H), 4.66 (d, J ¼ 4.0 Hz, 1H), 3.86 (d, J ¼ 12.5 Hz, 1H), 3.72 (d, J ¼ 12.5 Hz,
1H), 3.48 (d, 14.5 Hz, 1H), 2.75 (d, J ¼ 7.5 Hz, 1H), 2.56 (dd, J ¼ 14.5, 12.0 Hz, 1H),
2.30–2.38 (m, 1H), 2.19 (dd, J ¼ 12.5, 6.0 Hz, 1H), 2.17 (s, 1H), 2.13 (s, 3H), 1.88
(dd, J ¼ 13.3, 5.3 Hz, 1H), 1.58 (td, J ¼ 13.5, 6.0 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H);
13C NMR: (125 MHz, CDCl3) d 178.7, 175.0, 170.2, 85.5, 84.4, 80.2, 70.9, 66.1, 55.2,
54.0, 48.7, 43.6, 34.6, 28.6, 24.3, 20.9, 19.2; IR (film, cm21): 3,473 (broad), 2,947,
2,929, 2,873, 1,763, 1,751, 1,462, 1,379, 1,329, 1,286, 1,236, 1,178, 1,119, 1,066, 1,038;
HRMS (ESI) m/z calc’d for C17H22O8Na [M þ Na]þ: 377.1212, found 377.1205;
[a]2D5 ¼ þ132.78 (c ¼ 0.32, EtOH).
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´
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cytochrome P450-catalyzed hydroxylation reactions. Acc. Chem. Res. 33,
449–455 (2000) and references therein.
Hydroxylactone [(1)-32b]. 1H NMR (500 MHz, CDCl3) d 5.11 (dd, J ¼ 11.3,
3.8 Hz, 1H), 4.65 (d, J ¼ 4.0 Hz, 1H), 3.78 (d, J ¼ 12.5 Hz, 1H), 3.58 (d, J ¼ 12.5 Hz,
1H), 2.88 (ABq, Dy ¼ 34.9 Hz, Jab ¼ 15.0 Hz, 1H), 2.87 (ABq, Dy ¼ 22.4 Hz, Jab
¼
15.0 Hz, 1H), 2.77 (d, J ¼ 7.5 Hz, 1H), 2.31–2.39 (m, 1H), 2.20 (dd, J ¼ 12.5, 6.0 Hz,
221
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